Antibiotic composition

ABSTRACT

Disclosed are antibiotic products for delivering at least two different antibiotics, wherein the products are comprised of at least three or four dosage forms with different release profiles and the at least two different antibiotics comprise at least one protein synthesis inhibiting antibiotic and at least one non-protein synthesis inhibiting antibiotic.

[0001] This application is a continuation-in-part of U.S. applicationSer. No. 10/093,321, filed Mar. 7, 2002, which is a continuation-in-partof U.S. application Ser. No. 09/791,983, filed Feb. 23, 2001, whichclaims the priority of U.S. Provisional Application Serial No.60/184,545 filed on Feb. 24, 2000, the disclosures of each of which arehereby incorporated by reference in their entireties.

[0002] The instant application also claims the priority of InternationalApplication PCT/US03/07118, filed Mar. 7, 2003, which application claimsthe priority of U.S. application Ser. No. 10/093,321, filed Mar. 7,2002, which is a continuation-in-part of U.S. application Ser. No.09/791,983, filed Feb. 23, 2001, which claims the priority of U.S.Provisional Application Serial No. 60/184,545 filed on Feb. 24, 2000.The disclosures of each of the foregoing applications are herebyincorporated by reference in their entireties.

[0003] This invention relates to antibiotic compositions and the usethereof. More particularly, this invention relates to a composition forthe delivery of two or more antibiotics, and the use thereof.

[0004] In many cases, it is desirable to employ two differentantibiotics in the treatment of a bacterial infection, in that suchantibiotics may have complementary mechanisms of action that facilitatetreatment of the bacterial infection.

[0005] The present invention is directed to a new and improved productthat delivers two antibiotics one of which is a protein synthesisinhibiting antibiotic, and the other of which is a non-protein synthesisinhibiting antibiotic. In one aspect, the present invention relates to aproduct that delivers Clarithromycin and Amoxicillin.

[0006] In accordance with an aspect of the present invention, there isprovided an antibiotic product for delivering at least two differentantibiotics that is comprised of at least three dosage forms eachcomprised of at least one antibiotic and a pharmaceutically acceptablecarrier, with one of the dosage forms including at least one of the atleast two antibiotics and at least one dosage form including at least asecond antibiotic of the at least two antibiotics, wherein one of theantibiotics is a protein synthesis inhibiting antibiotic such asClarithromycin, and the other antibiotic is a non-protein synthesisinhibiting antibiotic such as Amoxicillin.

[0007] Thus, for example, each of the dosage forms may include two ormore antibiotics, or one or two of the dosage forms may include only oneof the two or more antibiotics and each of the remaining dosage formsmay include only one or more of the different antibiotics or two or moreof the antibiotics. Thus, in accordance with this aspect of theinvention, there is an antibiotic product for delivering at least twodifferent antibiotics wherein the product includes at least three dosageforms wherein each of the at least two antibiotics is present in atleast one of the three dosage forms. In each case, one of theantibiotics is a protein synthesis inhibiting antibiotic such asClarithromycin, and the other antibiotic is a non-protein synthesisinhibiting antibiotic such as Amoxicillin.

[0008] In accordance with an embodiment of the present invention, thereis provided an antibiotic product for delivering at least two differentantibiotics that is comprised of at least three dosage forms eachcomprised of at least one antibiotic and a pharmaceutically acceptablecarrier, with one of the dosage forms including at least one of the atleast two antibiotics and at least one dosage form including at least asecond antibiotic of the at least two antibiotics, wherein one of theleast two antibiotics is a protein synthesis inhibiting antibiotic suchas Clarithromycin, and the other antibiotic is a non-protein synthesisinhibiting antibiotic such as Amoxicillin. In a preferred embodimenteach dosage form includes at least one of such two antibiotics. In aparticularly preferred embodiment, each dosage form includes only one ofthe two antibiotics with each of the two antibiotics being present in atleast one of the three dosage forms.

[0009] In a preferred embodiment each of the dosage forms has adifferent release profile, with one of the dosage forms being animmediate release dosage form.

[0010] In another aspect, the present invention is directed to treatinga bacterial infection by administering to a host in need thereof anantibiotic product as hereinabove and hereinafter described.

[0011] Thus, in accordance with an aspect of the present invention,there is provided a single or unitary antibiotic product that hascontained therein at least three antibiotic dosage forms, each of whichhas a different release profile, whereby the antibiotic contained ineach of the at least three dosage forms is released at different times,and wherein at least one of the dosage forms includes at least a proteinsynthesis inhibiting antibiotic such as Clarithromycin, and at least oneof the dosage forms includes at least a non-protein synthesis inhibitingantibiotic such as Amoxicillin. One or more of the dosage forms mayinclude both Clarithromycin and Amoxicillin.

[0012] In accordance with a further aspect of the invention, theantibiotic product may be comprised of at least four different dosageforms, each of which starts to release the antibiotic contained thereinat different times after administration of the antibiotic product, witheach of the dosage forms including at least one of either a proteinsynthesis inhibiting antibiotic such as Clarithromycin, or a non-proteinsynthesis inhibiting antibiotic such as Amoxicillin, such that at leastone dosage form contains a protein synthesis inhibiting antibiotic andat least one dosage form contains at least a non-protein synthesisanitbiotic.

[0013] The antibiotic product generally does not include more than fivedosage forms with different release times.

[0014] In accordance with a preferred embodiment, the antibiotic producthas an overall release profile such that when administered the maximumserum concentration of the total antibiotic released from the product isreached in less than twelve hours, preferably in less than eleven hours.In an embodiment, the maximum serum concentration of the totalantibiotic released from the antibiotic product is achieved no earlierthan four hours after administration.

[0015] In accordance with one preferred embodiment of the invention, oneof the at least three dosage forms is an immediate release dosage formwhereby initiation of release of antibiotic therefrom is notsubstantially delayed after administration of the antibiotic product.The second and third of the at least three dosage forms is a delayeddosage form (which may be a pH sensitive or a non-pH sensitive delayeddosage form, depending on the type of antibiotic product), wherebyantibiotic released therefrom is delayed until after initiation ofrelease of antibiotic from the immediate release dosage form. Moreparticularly, antibiotic release from the second of the at least twodosage forms achieves a C_(max) (maximum serum concentration in theserum) at a time after antibiotic released from the first of the atleast three dosage forms achieves a C_(max) in the serum, and antibioticreleased from the third dosage form achieves a C_(max) in the serumafter the C_(max) of antibiotic released from the second dosage form.

[0016] In one embodiment, the second of the at least two dosage formsinitiates release of antibiotic contained therein at least one hourafter the first dosage form, with the initiation of the releasetherefrom generally occurring no more than six hours after initiation ofrelease of antibiotic from the first dosage form of the at least threedosage forms.

[0017] In general, the immediate release dosage form produces a C_(max)for antibiotic released therefrom within from about 0.5 to about 2hours, with the second dosage form of the at least three dosage formsproducing a C_(max) for antibiotic released therefrom in no more thanabout four hours. In general, the C_(max) for such second dosage form isachieved no earlier than two hours after administration of theantibiotic product; however, it is possible within the scope of theinvention to achieve C_(max) in a shorter period of time.

[0018] As hereinabove indicated, the antibiotic product may contain atleast three or at least four or more different dosage forms. Forexample, the antibiotic released from the third dosage form reaches aC_(max) at a time later than the C_(max) is achieved for antibioticreleased from each of the first and second dosage forms. In a preferredembodiment, release of antibiotic from the third dosage form is startedafter initiation of release of antibiotic from both the first dosageform and the second dosage form. In one embodiment, C_(max) forantibiotic release from the third dosage form is achieved within eighthours.

[0019] In another embodiment, the antibiotic product contains at leastfour dosage forms, with each of the at least four dosage forms havingdifferent release profiles, whereby antibiotic released from each of theat least four different dosage forms achieves a C_(max) at a differenttime.

[0020] As hereinabove indicated, in a preferred embodiment, irrespectiveof whether the antibiotic contains at least three or at least fourdifferent dosage forms each with a different release profile, C_(max)for all the antibiotic released from the antibiotic product is achievedin less than twelve hours, and more generally is achieved in less thaneleven hours.

[0021] In a preferred embodiment, the antibiotic product is a once a dayproduct, whereby after administration of the antibiotic product, nofurther product is administered during the day; i.e., the preferredregimen is that the product is administered only once over a twenty-fourhour period. Thus, in accordance with the present invention, there is asingle administration of an antibiotic product with the antibiotic beingreleased in a manner such that overall antibiotic release is effectedwith different release profiles in a manner such that the overallC_(max) for the antibiotic product is reached in less than twelve hours.The term single administration means that the total antibioticadministered over a twenty-four hour period is administered at the sametime, which can be a single tablet or capsule or two or more thereof,provided that they are administered at essentially the same time.

[0022] Thus in accordance with an aspect of the invention, there isprovided a single dosage antibiotic product comprised of at least threeantibiotic dosage forms each having a different release profile witheach of the dosage forms including at least one of either a proteinsynthesis inhibiting antibiotic such as Clarithromycin, or a non-proteinsynthesis inhibiting antibiotic such as Amoxicillin, such that at leastone dosage form contains a protein synthesis inhibiting antibiotic andat least one dosage form contains at least a non-protein synthesisanitbiotic. Each of the dosage forms of antibiotic in a pharmaceuticallyacceptable carrier may have one or more antibiotics.

[0023] In one embodiment, the first dosage form contains a firstantibiotic which is one of either a protein synthesis inhibitingantibiotic or a non-protein synthesis inhibiting antibiotic and is freeof the other antibiotic, and in a preferred embodiment contains only thefirst antibiotic; the second dosage form contains a second antibioticwhich is the other of either a protein synthesis inhibiting antibioticor a non-protein synthesis inhibiting antibiotic and is free of thefirst antibiotic, and in a preferred embodiment contains only secondantibiotic; and the third dosage form contains the first antibiotic andis free of the second antibiotic, and in a preferred embodiment containsonly the first antibiotic; and if a fourth dosage form is used, suchfourth dosage form contains the second antibiotic and is free of thefirst antibiotic; and in a preferred embodiment bacteria are exposed toalternating pulses of the two antibiotics of the hereinabove describedfirst and second antibiotics. In a particularly preferred embodiment thefirst and second antibiotics are chosen from the group consisting ofClarithromycin and Amoxicillin.

[0024] It is to be understood that when it is disclosed herein that adosage form initiates release after another dosage form, suchterminology means that the dosage form is designed and is intended toproduce such later initiated release. It is known in the art, however,notwithstanding such design and intent, some “leakage” of antibiotic mayoccur. Such “leakage” is not “release” as used herein.

[0025] If at least four dosage forms are used, the fourth of the atleast four dosage form may be a sustained release dosage form or adelayed release dosage form. If the fourth dosage form is a sustainedrelease dosage form, even though C_(max) of the fourth dosage form ofthe at least four dosage forms is reached after the C_(max) of each ofthe other dosage forms is reached, antibiotic release from such fourthdosage form may be initiated prior to or after release from the secondor third dosage form.

[0026] In one embodiment of the invention, one of the antibiotics of theantibiotic pairs as hereinabove and hereinafter described is a proteinsynthesis inhibiting antibiotic and the other antibiotic of theantibiotic pair is a non-protein synthesis inhibiting antibiotic.

[0027] The terminology “protein synthesis inhibiting antibiotic” meansan agent that disrupts the bacterial ribosome cycle through whichpolypeptide chain initiation and elongation is normally effected. Thereare multiple points in the ribosome cycle at which this can occur.

[0028] The terminology “non-protein synthesis inhibiting antibiotic”means antibiotics other than protein synthesis inhibiting antibiotics.

[0029] As non-limiting representative examples of “protein synthesisinhibiting antibiotics” there may be mentioned: the aminoglycosides suchas streptomycin, amikacin, and tobramycin; the macrolides such aserythromycin, clarithromycin, and lincomycin; the tetracyclines such astetracycline, doxycycline, chlortetracycline, and minocycline; theoxaxolidinones such as linezolid; fusidic acid; and chloramphenicol.

[0030] As non-limiting representative examples of “non-protein synthesisinhibiting antibiotics” there may be mentioned: the beta-lactampenicillins such as penicillin, amoxicillin, dicloxacillin, andampicillin; the beta lactam cephalsporins such as cefotaxime,cefuroxime, cefaclor, and ceftriaxone; the beta lactam carbapenems suchas imipenem and meropenem; the quinolones such as ciprofloxacin,moxifloxacin, and levofloxacin; the sulfonamides such as sulfanilimideand sulfamethoxazole; metronidazole; rifampin; vancomycin; andnitrofurantoin.

[0031] In a preferred embodiment such two antibiotics are delivered inalternating pulses.

[0032] In a particularly preferred embodiment of the present invention,there is provided an antibiotic composition that includes threedifferent dosage forms: the first dosage form providing an initialdosage of a first antibiotic that is a protein synthesis inhibitingantibiotic and wherein the first dosage form is free of antibiotics thatare not protein synthesis inhibiting antibiotics and in one preferredembodiment contains only one antibiotic; the second dosage formproviding an initial dosage of a second antibiotic that is not a proteinsynthesis inhibiting antibiotic and wherein the second dosage form isfree of antibiotics that are protein synthesis inhibiting antibioticsand in one preferred embodiment contains only one antibiotic; and thethird dosage form providing an additional dosage of said firstantibiotic that is a protein synthesis inhibiting antibiotic and whereinthe third dosage form is free of antibiotics that are not proteinsynthesis inhibiting antibiotics and in one preferred embodimentcontains only one antibiotic. The first dosage form is an immediaterelease dosage form; and the second and third dosage forms are delayedrelease dosage forms.

[0033] In another preferred embodiment of the present invention, thereis provided an antibiotic composition that includes four differentdosage forms: the first dosage form providing an initial dosage of afirst antibiotic that is a protein synthesis inhibiting antibiotic andwherein the first dosage form is free of antibiotics that are notprotein synthesis inhibiting antibiotics and in a preferred embodimentcontains only one antibiotic; the second dosage form providing aninitial dosage of a second antibiotic that is not a protein synthesisinhibiting antibiotic and wherein the second dosage form is free ofantibiotics that are protein synthesis inhibiting antibiotics and in apreferred embodiment contains only one antibiotic; the third dosage formproviding an additional dosage of said first antibiotic that is aprotein synthesis inhibiting antibiotic and wherein the third dosageform is free of antibiotics that are not protein synthesis inhibitingantibiotics and in a preferred embodiment contains only one antibiotic;and the fourth dosage form providing an additional dosage of said secondantibiotic that is not a protein synthesis inhibiting antibiotic andwherein the fourth dosage form is free of antibiotics that are proteinsynthesis inhibiting antibiotics and in a preferred embodiment containsonly one antibiotic. The first dosage form is an immediate releasedosage form; the second and third dosage forms are delayed releasedosage forms; and the fourth dosage form is optionally a delayed releasedosage form or a sustained release dosage form, preferably a delayedrelease dosage form.

[0034] Particularly advantageous formulations of the immediatelypreceding embodiments of the present invention are those that compriseClarithromycin, a protein synthesis inhibiting antibiotic as one of theantibiotics, and Amoxicillin, a non-protein synthesis inhibitingantibiotic as the other antibiotic. In these formulations a first,immediate release dosage form contains an initial dosage ofClarithromycin and is free of any non-protein synthesis inhibitingantibiotics; a second, delayed release dosage form contains an initialdosage of Amoxicillin and is free of any protein synthesis inhibitingantibiotics; and a third, delayed release dosage form provides anadditional dosage of Clarithromycin and is free of any non-proteinsynthesis inhibiting antibiotics. An optional fourth, dosage formprovides an additional dosage of Amoxicillin and is free of any proteinsynthesis inhibiting antibiotics. This fourth dosage form is a delayedrelease or a sustained release dosage form, preferably a delayed releasedosage form.

[0035] In accordance with an aspect of the present invention, there isprovided an antibiotic composition that is a mixture of antibioticcompositions or dosage forms wherein said composition contains a firstcomposition or dosage form comprising a first antibiotic and apharmaceutically acceptable carrier; a second composition or dosage formcomprising the first antibiotic and a pharmaceutically acceptablecarrier; a third composition or dosage form comprising a secondantibiotic different from the first antibiotic and a pharmaceuticallyacceptable carrier; and a fourth composition or dosage form comprisingthe second antibiotic and a pharmaceutically acceptable carrier; whereinthe second and third compositions each have a release profile thatprovides a maximum serum concentration of the first antibiotic releasedfrom the second composition and a maximum serum concentration for thesecond antibiotic released from the third composition at a time afterthe first antibiotic released from the first composition reaches amaximum serum concentration, and wherein the fourth composition has arelease profile that provides for a maximum serum concentration of thesecond antibiotic released from the fourth composition at a time afterthe antibiotics released from the second and third compositions reach amaximum serum concentration. The first antibiotic is either a proteinsynthesis inhibiting antibiotic such as Clarithromycin or a non-proteinsynthesis inhibiting antibiotic such as Amoxicillin, and the secondantibiotic is the other of either a protein synthesis inhibitingantibiotic such as Clarithromycin or a non-protein synthesis inhibitingantibiotic such as Amoxicillin.

[0036] In one embodiment, the release profiles of the second and thirdcomposition are such that the maximum serum concentration of the firstantibiotic released from the second composition, and the maximum serumconcentration of the second antibiotic released from the thirdcomposition are reached at approximately the same time, or where thefirst antibiotic reaches a maximum serum concentration before or afterthe second antibiotic reaches a maximum serum concentration.

[0037] In effect, in accordance with one preferred embodiment of thepresent invention, there is provided a first pulse in which a firstantibiotic reaches a maximum serum concentration, a second pulse whereina further dosage of the first antibiotic, and an initial dosage of thesecond antibiotic reach a maximum serum concentration at a time afterthe first pulse of the first antibiotic reaches a maximum serumconcentration, and a third pulse wherein an additional dosage of thesecond antibiotic reaches a maximum serum concentration at a time afterthe maximum serum concentration is reached for each of the first andsecond antibiotic dosages provided in the second pulse.

[0038] In a preferred embodiment of the present invention, the firstdosage of the first antibiotic achieves a maximum serum concentrationwithin four hours after administration of the antibiotic composition;the second dosage of the first antibiotic and the first dosage of thesecond antibiotic each reach a maximum serum concentration within fourto eight hours after administration of the antibiotic composition; andthe second dosage of the second antibiotic reaches a maximum serumconcentration within twelve hours after administration of the antibioticcomposition.

[0039] Thus, in accordance with an aspect of the present invention,there is provided an antibiotic composition that includes four differentdosage forms, with the first dosage form providing an initial dosage ofa first antibiotic, the second dosage form providing a further dosage ofthe first antibiotic; the third dosage form providing an initial dosageof a second antibiotic; and the fourth dosage form providing anadditional dosage of the second antibiotic, wherein the antibioticsreleased from the second and third dosage forms reach a maximum serumconcentration at a time after the antibiotic released from the firstdosage form reaches a maximum serum concentration, and the antibioticreleased from the fourth dosage form reaching a maximum serumconcentration at a time after the times at which the antibioticsreleased from each of the first, second, and third dosage forms reach amaximum serum concentration.

[0040] In one embodiment of the invention, the first dosage formprovides for immediate release, the second and third dosage formsprovide for a delayed release (pH or non pH dependent, with the seconddosage form preferably being a pH dependent release), and the fourthdosage form provides for pH dependent or non pH dependent releasepreferably non pH dependent release.

[0041] In formulating the antibiotic composition of the presentinvention, which contains four different dosage forms, as hereinabovedescribed, the first and second dosage forms each generally contain fromabout 30 percent to about 80 percent of either a protein synthesisinhibiting antibiotic such as Clarithromycin or a non-protein synthesisinhibiting antibiotic such as Amoxicillin; the third and fourth dosageforms each contain from about 30 percent to about 80 percent of theother of either a protein synthesis inhibiting antibiotic such asClarithromycin or a non-protein synthesis inhibiting antibiotic such asAmoxicillin. In formulating a composition comprised of such four dosageforms or units, each unit or dosage form is present in an amount of atleast 20 percent by weight, with each dosage form or unit being presentin the overall composition in an amount that generally does not exceed60 percent by weight.

[0042] Each of the first and second dosage forms include from 20% to 80%of the total dosage of the first antibiotic to be provided by thecomposition, and each of the first and second dosage forms may includethe same or different dosages of the first antibiotic.

[0043] Each of the third and fourth dosage forms include from 20% to 80%of the total dosage of the second antibiotic to be delivered by thecomposition, and each of the third and fourth units may have the same ordifferent dosages of the antibiotic.

[0044] In another embodiment the product as hereinabove described mayalso be formulated in a manner such that the product contains at leastthree dosage forms wherein each of the three dosage forms is a delayedrelease dosage form, with the product being free of an immediate releasedosage form. As hereinabove described, the product contains both aprotein synthesis inhibiting antibiotic such as Clarithromycin, and anon-protein synthesis inhibiting antibiotic such as Amoxicillin. In thisembodiment the overall Cmax is reached within 12 hours after initialrelease of antibiotic, i.e. Cmax is achieved in less than about twelvehours after initial release of antibiotic. As hereinabove described thisproduct may optionally contain a fourth dosage form. When such productcontains a fourth dosage form, such fourth dosage form is preferably adelayed release dosage form, but may otherwise be a sustained releasedosage form. As hereinabove described, in a preferred embodiment, theantibiotic product is a once a day product, whereby after administrationof the antibiotic product, no further product is administered during theday; i.e., the preferred regimen is that the product is administeredonly once over a twenty-four hour period. Thus, in accordance with thepresent invention, there is a single administration of an antibioticproduct with the antibiotic being released in a manner such that overallantibiotic release is effected with different release profiles in amanner such that the overall C_(max) for the antibiotic product isreached in less than twelve hours from the initial release ofantibiotic. The term single administration means that the totalantibiotic administered over a twenty-four hour period is administeredat the same time, which can be a single tablet or capsule or two or morethereof, provided that they are administered at essentially the sametime.

[0045] In formulating an antibiotic product in accordance with theinvention, in one embodiment, the immediate release dosage form of theproduct generally provides from about 20% to about 50% of the totaldosage of antibiotic to be delivered by the product, with such immediaterelease dosage form generally providing at least 25% of the total dosageof the antibiotic to be delivered by the product. In many cases, theimmediate release dosage form provides from about 20% to about 30% ofthe total dosage of antibiotic to be delivered by the product; however,in some cases it may be desirable to have the immediate release dosageform provide for about 45% to about 50% of the total dosage ofantibiotic to be delivered by the product.

[0046] The remaining dosage forms deliver the remainder of theantibiotic. If more than one delayed release dosage form is used, in oneembodiment, each of the delayed release dosage forms may provide aboutequal amounts of antibiotic; however, they may also be formulated so asto provide different amounts.

[0047] In one embodiment, where the composition contains one immediaterelease component and two delayed release components, the immediaterelease component provides from 20% to 35% (preferably 20% to 30%), byweight, of the total antibiotic; where there is three delayed releasecomponents, the immediate release component provides from 15% to 30%, byweight, of the total antibiotic; and where there are four delayedrelease components, the immediate release component provides from 10% to25%, by weight, of the total antibiotic.

[0048] With respect to the delayed release components, where there aretwo delayed release components, the first delayed release component (theone released earlier in time) provides from 30% to 60%, by weight, ofthe total antibiotic provided by the two delayed release components withthe second delayed release component providing the remainder of theantibiotic.

[0049] Where there are three delayed release components, the earliestreleased component provides 20% to 35% by weight of the total antibioticprovided by the three delayed release components, the next in timedelayed release component provides from 20% to 40%, by weight, of theantibiotic provided by the three delayed release components and the lastin time providing the remainder of the antibiotic provided by the threedelayed release components.

[0050] When there are four delayed release components, the earliestdelayed release component provides from 15% to 30%, by weight, the nextin time delayed release component provides from 15% to 30%, the next intime delayed release component provides from 20% to 35%, by weight, andthe last in time delayed release component provides from 20% to 35%, byweight, in each case of the total antibiotic provided by the fourdelayed release components.

[0051] The overall composition includes each of the antibiotics in atherapeutically effective amount. The specific amount(s) is dependant onthe antibiotic used, the disease or infection to be treated, and thenumber of times of day that the composition is to be administered.

[0052] The antibiotic composition of the present invention may beadministered for example, by any one of the following routes ofadministration: sublingual, transmucosal, transdermal, parenteral, oral,preferably by oral administration.

[0053] The antibiotic product of the present invention, as hereinabovedescribed, may be formulated for administration by a variety of routesof administration. For example, the antibiotic product may be formulatedin a way that is suitable for topical administration; administration inthe eye or the ear; rectal or vaginal administration; as nose drops; byinhalation; as an injectable; or for oral administration. In a preferredembodiment, the antibiotic product is formulated in a manner such thatit is suitable for oral administration.

[0054] For example, in formulating the antibiotic product for topicaladministration, such as by application to the skin, the at least twodifferent dosage forms, each of which contains an antibiotic, may beformulated for topical administration by including such dosage forms inan oil-in-water emulsion, or a water-in-oil emulsion. In such aformulation, the immediate release dosage form is in the continuousphase, and the delayed release dosage form is in a discontinuous phase.The formulation may also be produced in a manner for delivery of threedosage forms as hereinabove described. For example, there may beprovided an oil-in-water-in-oil emulsion, with oil being a continuousphase that contains the immediate release component, water dispersed inthe oil containing a first delayed release dosage form, and oildispersed in the water containing a third delayed release dosage form.

[0055] It is also within the scope of the invention to provide anantibiotic product in the form of a patch, which includes antibioticdosage forms having different release profiles, as hereinabovedescribed.

[0056] In addition, the antibiotic product may be formulated for use inthe eye or ear or nose, for example, as a liquid emulsion. For example,the dosage form may be coated with a hydrophobic polymer whereby adosage form is in the oil phase of the emulsion, and a dosage form maybe coated with hydrophilic polymer, whereby a dosage form is in thewater phase of the emulsion.

[0057] Furthermore, the antibiotic product with at least three differentdosage forms with different release profiles may be formulated forrectal or vaginal administration, as known in the art. This may take theform of a cream or emulsion, or other dissolvable dosage form similar tothose used for topical administration.

[0058] As a further embodiment, the antibiotic product may be formulatedfor use in inhalation therapy by coating the particles and micronizingthe particles for inhalation.

[0059] In a preferred embodiment, the antibiotic product is formulatedin a manner suitable for oral administration. Thus, for example, fororal administration, each of the dosage forms may be used as a pellet ora particle, with a pellet or particle then being formed into a unitarypharmaceutical product, for example, in a capsule, or embedded in atablet, or suspended in a liquid for oral administration.

[0060] Alternatively, in formulating an oral delivery system, each ofthe dosage forms of the product may be formulated as a tablet, with eachof the tablets being put into a capsule to produce a unitary antibioticproduct. Thus, for example, antibiotic products may include a firstdosage form in the form of a tablet that is an immediate release tablet,and may also include two or more additional tablets, each of whichprovides for a delayed release of the antibiotic, as hereinabovedescribed, whereby the C_(max) of the antibiotic released from each ofthe tablets is reached at different times, with the C_(max) of the totalantibiotic released from the antibiotic product being achieved in lessthan twelve hours.

[0061] The formulation of an antibiotic product including at least threedosage forms with different release profiles for different routes ofadministration is deemed to be within the skill of the art from theteachings herein. As known in the art, with respect to delayed release,the time of release can be controlled by the concentration ofantibiotics in the coating and/or the thickness of the coating.

[0062] As hereinabove indicated, the first and second antibioticsemployed in the antibiotic composition may be a wide variety ofproducts. In one embodiment, the combination of first and secondantibiotics that are used in the composition may be, for example, apenicillin and an aminoglycoside, such as gentamycin, tobramicin,amikacin or vancomycin. Another antibiotic composition that may beemployed is a combination of a sulfonamide, such as sulfamethoxasol,which would be combined with trimethoporim. In a preferred embodiment,the first and second, antibiotics are different antibiotics and each isfrom a different class of antibiotic.

[0063] The Immediate Release Component

[0064] The immediate release portion of this system can be a mixture ofingredients that breaks down quickly after administration to release theantibiotic. This can take the form of either a discrete pellet orgranule that is mixed in with, or compressed with, the other threecomponents.

[0065] The materials to be added to the antibiotics for the immediaterelease component can be, but are not limited to, microcrystallinecellulose, corn starch, pregelatinized starch, potato starch, ricestarch, sodium carboxymethyl starch, hydroxypropylcellulose,ydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose,chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linkedchitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol,sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose,polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol,Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs(PEG2000-1 0000) and high molecular weight PEGs (Polyox) with molecularweights above 20,000 daltons.

[0066] It may be useful to have these materials present in the range of1.0 to 60% (W/W).

[0067] In addition, it may be useful to have other ingredients in thissystem to aid in the dissolution of the drug, or the breakdown of thecomponent after ingestion or administration. These ingredients can besurfactants, such as sodium lauryl sulfate, sodium monoglycerate,sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitanmonooleate, glyceryl monostearate, glyceryl monooleate, glycerylmonobutyrate, one of the non-ionic surfactants such as the Pluronic lineof surfactants, or any other material with surface active properties, orany combination of the above.

[0068] These materials may be present in the rate of 0.05-15% (W/W).

[0069] The Delayed Release Component

[0070] The components in this composition are the same immediate releaseunit, but with additional polymers integrated into the composition, oras coatings over the pellet or granule.

[0071] Materials that can be used to obtain a delay in release suitablefor this component of the invention can be, but are not limited to,polyethylene glycol (PEG) with molecular weight above 4,000 daltons(Carbowax, Polyox), waxes such as white wax or bees wax, paraffin,acrylic acid derivatives (Eudragit), propylene glycol, andethylcellulose.

[0072] Typically these materials can be present in the range of 0.5-25%(W/W) of this component.

[0073] The Enteric Release Component

[0074] The components in this composition are the same as the immediaterelease component, but with additional polymers integrated into thecomposition, or as coatings over the pellet or granule.

[0075] The kind of materials useful for this purpose can be, but are notlimited to, cellulose acetate pthalate, Eudragit L, and other pthalatesalts of cellulose derivatives.

[0076] These materials can be present in concentrations from 4-20%(W/W).

[0077] The invention will be further described with respect to thefollowing examples; however the scope of the invention is not limitedthereby. All percentages stated in this specification are by weight,unless otherwise specified.

EXAMPLES

[0078] Immediate Release Component Ingredient Conc. (% W/W) Example 1:Amoxicillin 65% (W/W) Microcrystalline cellulose 20 Povidone 10Croscarmellose sodium 5 Example 2: Amoxicillin 55% (W/W)Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10Example 3: Amoxicillin 65% (W/W) Microcrystalline cellulose 20Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 4: Amoxicillin75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10Hydroxypropylcellulose 5 Example 5: Amoxicillin 75% (W/W) Polyethyleneglycol 8000 20 Polyvinylpyrrolidone 5 Example 6: Clarithromycin 65%(W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10Croscarmellose sodium 5 Example 7: Clarithromycin 75% (W/W)Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellosesodium 5 Example 8: Clarithromycin 75% (W/W) Polyethylene glycol 4000 10Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 9:Clarithromycin 75% (W/W) Polyethylene glycol 8000 20Polyvinylpyrrolidone 5 Example 10: Ciprofoxacin 65% (W/W)Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellosesodium 5 Example 11: Ciprofoxacin 75% (W/W) Microcrystalline cellulose15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 12:Ciprofoxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol2000 10 Hydroxypropylcellulose 5 Example 13: Cirpofoxacin 75% (W/W)Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 14:Ceftibuten 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol2000 10 Hydroxypropylcellulose 5 Example 15: Ceftibuten 75% (W/W)Polyethylene Glycol 4000 20 Polyvinylpyrrolidone 5

[0079] Delayed Release Component (Non-pH Dependant) Ingredient Conc. (%W/W) Example 16: Amoxicillin 65% (W/W) Microcrystalline cellulose 20Polyox 10 Croscarmellose sodium 5 Example 17: Amoxicillin 55% (W/W)Microcrystalline cellulose 25 Polyox 10 Glyceryl monooleate 10 Example18: Amoxicillin 65% (W/W) Polyox 20 Hydroxypropylcellulose 10Croscarmellose sodium 5 Example 19: Clarithromycin 70% (W/W) Polyox 20Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 20: Gentamicin20% (W/W) Sodium lauryl sulfate 2 Sodium monoglycerides 10 Sodiumdiglycerides 20 Diethyleneglycolmethylether 5 Microcrystalline cellulose43 Example 21: Gentamicin 10% (W/W) Glyvceryl behanate 30 Pluronic 10Carbopol 94P 30 Microcrystalline cellulose 20 Example 22: Gentamicin 25%(W/W) Carbopol 94P 35 Microcrystalline cellulose 20 Vitamin E TPGS 15Sodium monoglycerate 5 Example 23: Amikacin 25% (W/W) Carbopol 94P 10Sodium monoglycerate 15 Sodium diglycerate 15 Pluronic 10 Lactose 25Example 24: Gentamicin 30% (W/W) Triacetin 15 Capryol 90 5 PoloxamerSynperonic PE/F66 10 Cab-O-Sil 5 Microcrystalline cellulose 35

[0080] Enteric Release Component Example 25: Clarithromycin 70% (W/W)Hydroxypropylcellulose 15 pthalate 10 Croscarmellose sodium Example 26:Clarithromycin 75% (W/W) Polyethylene glycol 2000 10 Eudragit E 30D 15Example 27: Clarithromycin 40% (W/W) Lactose 50 Eudgragit E 30D 10Example 28: Ciprofoxacin 65% (W/W) Microcrystalline Cellulose 20Eudragit E 30D 10 Example 29: Ciprofoxacin 75% (W/W) MicrocrystallineCellulose 15 Hydroxypropylcellulose 10 pthalate Example 30: Ciprofoxacin80% (W/W) Lactose 10 Eudragit E 30D 10 Example 31: Ciprofoxacin 70%(W/W) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10 Example32: Ceftibuten 60% (W/W) Polyethylene glycol 2000 10 Lactose 20 EudragitE 30D 10 Example 33: Ceftibuten 70% (W/W) Microcrystalline cellulose 20Cellulose acetate pthalate 10 Example 34: Amoxicillin 65% (W/W)Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 35:Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Cellulose AcetatePthalate 10 Hydroxypropylmethylcellulose 10 Example 36: Amoxicillin 65%(W/W) Polyox 20 Hydroxypropylcellulose 10 pthalate 5 Eudragit E 30DExample 37: Amoxicillin 40% (W/W) Microcrystalline Cellulose 40Cellulose Acetate Pthalate 10 Example 38: Gentamicin 20% (W/W) Sodiumlauryl sulfate 2 Sodium monoglycerides 10 Sodium diglycerides 20Diethyleneglycolmethylether 5 Microcrystalline cellulose 30 Celluloseacetate pthalate 13 Example 39: Gentamicin 10% (W/W) Glyceryl behanate30 Pluronic 10 Carbopol 94P 10 Microcrystalline cellulose 20 EudragitE30D 20 Example 40: Gentamicin 25% (W/W) Carbopol 94P 15Microcrystalline cellulose 20 Vitamin E TPGS 15 Sodium Monoglycerate 5Eudragit E30D 20 Example 41: Amikacin 25% (W/W) Carbopol 94p 10 Sodiummonoglycerate 15 Sodium diglycerate 15 Pluronic 10 Lactose 15 Celluloseacetate pthalate 10 Example 42: Gentamicin 30% (W/W) Triacetin 15Capryol 90 5 Poloxamer SynperonicPE/F66 10 Cab-O-Sil 5 Microcrystallinecellulose 25 Eudragit E30D 10

[0081] Three Pulses

Example 43

[0082] 1. Antibiotic Matrix Pellet Formulation and Preparation Procedure(Immediate Release)

[0083] A. Pellet Formulation

[0084] The composition of the antibiotic matrix pellets provided inTable 1. TABLE 1 Composition of Antibiotic Pellets Component Percentage(%) Antibiotic 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 PurifiedWater Total 100

[0085] B. Preparation Procedure for Antibiotic Matrix Pellets

[0086] 1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupehigh shear granulator.

[0087] 1.2.2 Add 20% Povidone K29/32 binder solution slowly into thepowder blend under continuous mixing.

[0088] 1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0089] 1.2.4 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0090] 1.2.5 Dry the spheronized pellets at 50° C. overnight.

[0091] 1.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0092] The above procedure is used to make pellets of a first antibioticand pellets of a second different antibiotic.

[0093] 1.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0094] A. Dispersion Formulation

[0095] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the antibiotic matrix pellets is provided below in Table 2.TABLE 2 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

[0096] B. Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0097] 1.3.1 Suspend triethyl citrate and talc in deionized water.

[0098] 1.3.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0099] 1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0100] 1.3.4 Allow the coating dispersion to stir for one hour prior toapplication onto the antibiotic matrix pellets.

[0101] 1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0102] A. Dispersion Formulation

[0103] The composition of the aqueous Eudragit® S 100 dispersion appliedto the antibiotic matrix pellets is provided below in Table 3. TABLE 3Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content20.0 Polymer Content 12.0

[0104] B. Preparation Procedure for an Eudragit® S 100 AqueousDispersion Part I:

[0105] (i) Dispense Eudragit® S 100 powder in deionized water withstirring.

[0106] (ii) Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0107] (iii) Allow the partially neutralized dispersion to stir for 60minutes.

[0108] (iv) Add triethyl citrate drop-wise into the dispersion withstirring. Stir for about 2 hours prior to the addition of Part B.

[0109] Part II:

[0110] (i) Disperse talc in the required amount of water

[0111] (ii) Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0112] (iii) Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0113] 1.5 Coating Conditions for the Application of Aqueous CoatingDispersions

[0114] The following coating parameters are used to coat matrix pelletswith each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous filmcoating. Coating Equipment STREA 1 ™ Table Top Laboratory Fluid BedCoater Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet AirTemperature 40 to 45° C. Outlet Air Temperature 30 to 33° C. AtomizationAir Pressure 1.8 Bar Pump Rate 2 gram per minute

[0115] (i) Coat matrix pellets with L30 D-55 dispersion such that youapply 12% coat weight gain to the pellets.

[0116] (ii) Coat matrix pellets with S100 dispersion such that you apply20% coat weight gain to the pellets.

[0117] 1.6 Encapsulation of the Antibiotic Pellets

[0118] Pellets are filled into size 00 hard gelatin capsules at a ratioof 30%: 30%: 40%: Immediate-release matrix pellets uncoated, L30 D-55coated pellets and S100 coated pellets respectively.

[0119] The capsule is filled with the three different pellets to achievea the desire dosage.

[0120] The immediate release matrix pellets include the firstantibiotic, the L30 D-55 coated pellets are made by coating matrixpellets that contain the second antibiotic and the S100 coated pelletsare made by coating matrix pellets that contain the first antibiotic.

[0121] Three Pulses

Example 44

[0122] Antibiotic Pellet Formulation and Preparation Procedure

[0123] 44.1 Pellet Formulations for Subsequent Coating

[0124] The composition of the Antibiotictrihydrate matrix pelletsprovided in Table 4. TABLE 4 Composition of AntibioticMatrix PelletsComponent Percentage (%) AntibioticTrihydrate powder 92 Avicel PH 1017.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0125] 44.2 Preparation Procedure for Antibiotic Matrix Pellets

[0126] 44.2.1 Blend Antibioticand Avicel® PH 101 using a low shearblender.

[0127] 44.2.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0128] 44.2.3 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator is 0.8 mm.

[0129] 44.2.4 Spheronize the extrudate using a QJ-230.5 pheronizer usinga small cross section plate.

[0130] 44.2.5Dry the spheronized pellets at 60° C. using a fluid beddryer until the exhaust temperature reaches 40° C.

[0131] 44.2.6 Pellets between 20 and 40 Mesh were collected for furtherprocessing.

[0132] 44.2.7 The above procedure is used to produce pellets thatcontain a first antibiotic and pellets that contain a second anddifferent antibiotic.

[0133] 44.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0134] 44.3.1 Dispersion Formulation

[0135] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the Antibioticmatrix pellets is provided below in Table 5.TABLE 5 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5

[0136] 44.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0137] 44.4.1 Suspend triethyl citrate and talc in deionized water.

[0138] 44.4.2 The TEC/talc suspension is mixed using laboratory mixer.

[0139] 44.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L30 D-55 latex dispersion while stirring.

[0140] 44.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the Antibioticmatrix pellets.

[0141] 44.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0142] 44.5.1 Dispersion Formulation

[0143] The composition of the aqueous Eudragit® S 100 dispersion appliedto the Antibioticmatrix pellets is provided below in Table 6. TABLE 6Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate5.0 Water 64.9 Part B Talc 5.0 Water 10.0 Solid Content 25.0 PolymerContent 10.0

[0144] 44.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0145] Part A:

[0146] 44.6.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0147] 44.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0148] 44.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

[0149] 44.6.4 Add triethyl citrate drop-wise into the dispersion withstirring and let stir overnight prior to the addition of Part B.

[0150] Part B:

[0151] 44.6.5 Disperse talc in the required amount of water

[0152] 44.6.6 Stir the dispersion using an overhead laboratory mixer.

[0153] 44.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0154] 44.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0155] The following coating parameters are used for both the Eudragit®L 30 D-55 and Eudragit® S 100 aqueous film coating processes. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45°C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure 1.8 BarPump Rate 2-6 gram per minute

[0156] 44.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 20% coat weight gain to the pellets.

[0157] 44.7.2 Coat matrix pellets with S100 dispersion such that youapply 37% coat weight gain to the pellets.

[0158] 44.8 Preparation of AntibioticGranulation (Immediate ReleaseComponent) for tabletting TABLE 7 Composition of AntibioticGranulationComponent Percentage (%) AntibioticTrihydrate powder 92 Avicel PH 1017.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100

[0159] 44.8.1 Blend Antibioticand Avicel® PH 101 using a low shearblender.

[0160] 44.8.2 Add the hydroxypropyl methylcellulose binder solutionslowly into the powder blend under continuous mixing.

[0161] 44.8.3 Dry the granulation at 60° C. using a fluid bed dryeruntil the exhaust temperature reaches 40° C.

[0162] 44.8.4 Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0163] 44.9 Tabletting of the AntibioticPellets TABLE 8 Composition ofAntibioticTablets Component Percentage (%) First antibiotiogranules 32.5Avicel PH 200 5.0 Second antibioticL30D-55 coated pellets 30 FirstantibioticS100 coated pellets 30 Colloidal silicon dioxide 1.5 Magnesiumstearate 1.0 Total 100

[0164] 44.9.1 Blend the Antibioticgranules, Avicel PH-200,Antibioticpellets and colloidal silicon dioxide for 15 minutes in atumble blender.

[0165] 44.9.2 Add the magnesium stearate to the blender, and blend for 5minutes.

[0166] 44.9.3 Compress the blend on a rotary tablet press.

[0167] 44.9.4 The fill weight should be adjusted to achieve the desireddosage.

[0168] Four pulses

EXAMPLE 45

[0169] 1 Antibiotic Matrix Pellet Formulation and Preparation Procedure

[0170] 45.1 Pellet Formulation

[0171] The composition of the antibiotic matrix pellets provided inTable 9. TABLE 9 Composition of Antibiotic Pellets Component Percentage(%) Antibiotic 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 PurifiedWater Total 100

[0172] 45.2 Preparation Procedure for Antibiotic Matrix Pellets

[0173] 45.2.1 Blend antibiotic and Avicel® PH 101 using a Robot Coupehigh shear granulator.

[0174] 45.2.2 Add 20% Povidone K29/32 binder solution slowly into thepowder blend under continuous mixing.

[0175] 45.2.3 Extrude the wet mass using an LCI Bench Top Granulator.The diameter of the screen of the Bench Top Granulator was 1.0 mm.

[0176] 45.2.4 Spheronize the extrudate using a Model SPH20 CalevaSpheronizer.

[0177] 45.2.5 Dry the spheronized pellets at 50° C. overnight.

[0178] 45.2.6 Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0179] 45.2.7 The above procedure is used to prepare pellets thatcontain a first antibiotic and pellets that contain a second antibiotic.

[0180] 45.3 Preparation of an Eudragit® L 30 D-55 Aqueous CoatingDispersion

[0181] 45.3.1 Dispersion Formulation

[0182] The composition of the aqueous Eudragit L30D-55 dispersionapplied to the antibiotic matrix pellets is provided below in Table 10.TABLE 10 Eudragit ® L 30 D-55 Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc 8.0Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9

[0183] 45.4 Preparation Procedure for an Eudragit® L 30 D-55 AqueousDispersion

[0184] 45.4.1 Suspend triethyl citrate and talc in deionized water.

[0185] 45.4.2 The TEC/talc suspension is then homogenized using aPowerGen 700 high shear mixer.

[0186] 45.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30D-55 latex dispersion while stirring.

[0187] 45.4.4 Allow the coating dispersion to stir for one hour prior toapplication onto the antibiotic matrix pellets.

[0188] 45.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

[0189] 45.5.1 Dispersion Formulation

[0190] The composition of the aqueous Eudragit® S 100 dispersion appliedto the antibiotic matrix pellets is provided below in Table 11. TABLE 11Eudragit ® S 100 Aqueous Coating Dispersion Component Percentage (%)Part A Eudragit ® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate6.0 Purified Water 65.9 Part B Talc 2.0 Purified Water 8.0 Solid Content20.0 Polymer Content 12.0

[0191] 45.6 Preparation Procedure for an Eudragit® S 100 AqueousDispersion

[0192] Part A:

[0193] 45.6.1 Dispense Eudragit® S 100 powder in deionized water withstirring.

[0194] 45.6.2 Add ammonium hydroxide solution drop-wise into thedispersion with stirring.

[0195] 45.6.3 Allow the partially neutralized dispersion to stir for 60minutes.

[0196] 45.6.4 Add triethyl citrate drop-wise into the dispersion withstirring. Stir for about 2 hours prior to the addition of Part B.

[0197] Part B:

[0198] 45.6.5 Disperse talc in the required amount of water

[0199] 45.6.6 Homogenize the dispersion using a PowerGen 700D high shearmixer.

[0200] 45.6.7 Part B is then added slowly to the polymer dispersion inPart A with a mild stirring.

[0201] 45.7 Coating Conditions for the Application of Aqueous CoatingDispersions

[0202] The following coating parameters are used for coating with eachof the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spraynozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40to 45° C. Outlet Air Temperature 30 to 33° C. Atomization Air Pressure1.8 Bar Pump Rate 2 gram per minute

[0203] 45.7.1 Coat matrix pellets with L30 D-55 dispersion such that youapply 12% coat weight gain to the pellets.

[0204] 45.7.2 Coat matrix pellets with L30 D-55 dispersion such that youapply 30% coat weight gain to the pellets.

[0205] 45.7.3 Coat matrix pellets with S100 dispersion such that youapply 20% coat weight gain to the pellets.

[0206] 45.8 Encapsulation of the Antibiotic Pellets

[0207] Pellets are filled into size 00 hard gelatin capsules at a ratioof 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weightgain and S100 coated pellets respectively. The capsule is filled withthe four different pellets to achieve the desired dosage.

[0208] The immediate release pellets contain the first antibiotic; theL30 D-55 12% weight gain coated pellets containe the second antibiotic;the L30 D-55 30% weight gain coated pellets contain the first antibioticand the S100 coated pellets contain the second antibiotic.

Example 46

[0209] Amoxicillin Pellet Formulation and Preparation Procedure

[0210] Pellet Formulations

[0211] The composition of the Amoxicillin trihydrate pellets provided inTable 12. TABLE 12 Composition of Amoxicillin Pellets ComponentPercentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 101 6.0Polyoxyl 35 Castor Oil* 1.0 Hydroxypropyl methylcellulose, NF* 1.0Purified Water ** Total 100

[0212] Preparation Procedure for Amoxicillin Pellets

[0213] Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

[0214] Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oilbinder solution slowly into the powder blend under continuous mixing.

[0215] Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator is 0.8 mm.

[0216] Spheronize the extrudate using a QJ-230 Spheronizer using a smallcross section plate.

[0217] Dry the spheronized pellets at 60° C. using a fluid bed dryeruntil the exhaust temperature reaches 40° C.

[0218] Pellets between 20 and 40 Mesh were collected for furtherprocessing.

[0219] Amoxicillin Enteric-Release Pellet Formulation and PreparationProcedure

[0220] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D AqueousCoating Dispersion Dispersion Formulation

[0221] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30Daqueous coating dispersion applied to the amoxicillin pellets isprovided below in Table 13. TABLE 13 Eudragit ® L 30 D-55/Eudragit NE30D Aqueous Coating Dispersion Component Percentage (%) Eudragit ® L30D-55 44.4 Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9Purified Water* 38.6 Solid Content 20.6 Polymer Content 16.4

[0222] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30DAqueous Dispersion

[0223] Heat purified water to 75-80° C. and then add triethyl citrate(TEC) and Imwitor 900. Homogenize dispersion until temperature is lessthan 55° C.

[0224] The TEC/Imwitor 900 dispersion is then stirred until thetemperature is less than 35° C.

[0225] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latexdispersion and stir for at least 30 minutes.

[0226] Add Eudragit NE 30D to the Eudragit L30DTEC/Imwitor 900dispersion and stir for at least 10 minutes.

[0227] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0228] Continue to stir the dispersion until the coating process iscomplete.

[0229] Coating Conditions for the Application of EudragitL30D-55/Eudragit NE 30DAqueous Coating Dispersion

[0230] The following coating parameters were used for coating of theEudragit® L 30 D-55/Eudragit NE30D film coating dispersion. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 45° C.Outlet Air Temperature 32 to 35° C. Atomization Air Pressure 1.6 BarPump Rate 3-4 gram per minute

[0231] Coat Amoxicillin pellets with Eudragit L30 D-55/Eudragit NE 30Dfilm coating dispersion such that you apply 20% coat weight gain to thepellets.

[0232] Amoxicillin Delayed Enteric-Release Pellets Formulation andPreparation Procedure

[0233] Preparation of an AQOAT AS-HF Aqueous Coating Dispersion

[0234] Dispersion Formulation

[0235] The composition of the aqueous AQOAT AS-HF aqueous coatingdispersion applied to the amoxicillin pellets is provided below in Table14. TABLE 14 AQOAT AS-HF Aqueous Coating Dispersion Component Percentage(%) AQOAT AS-HF 7.0 Triethyl Citrate 2.0 Talc 2.1 Sodium lauryl sulfate0.2 Purified Water* 88.7 Solid Content 11.3 Polymer Content 7.0

[0236] Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion

[0237] Add triethyl citrate (TEC) to the purified water with stirring.

[0238] Add the sodium lauryl sulfate (SLS) to the TEC dispersion withstirring and completely until completely dissolved.

[0239] Add the AQOAT to the TEC/SLS dispersion and stir for at least 30minutes.

[0240] Add the talc to the AQOAT dispersion and until completely mixedand for at least 30 minutes.

[0241] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0242] Continue to stir the dispersion until the coating process iscomplete.

[0243] Coating Conditions for the Application of AQOAT AS-HF AqueousCoating Dispersion

[0244] The following coating parameters were used for coating of theAQOAT AS-HF film coating dispersion. Coating Equipment STREA 1 ™ TableTop Laboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm MaterialCharge 300 gram Inlet Air Temperature 48° C. Outlet Air Temperature 27°C. Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram per minute

[0245] Coat amoxicillin pellets with AQOAT AS-HF film coating dispersionsuch that you apply 30-35% coat weight gain to the pellets.

[0246] Amoxicillin Colonic-Release Pellet Formulation and PreparationProcedure

[0247] Preparation of an Eudragit® FS 30D Aqueous Coating DispersionDispersion Formulation

[0248] The composition of the aqueous Eudragit® FS 30D dispersionapplied to the Amoxicillin pellets is provided below in Table 15. TABLE15 Eudragit ® FS 30D Aqueous Coating Dispersion Component Percentage (%)Eudragit ® FS 30D 54.8 Triethyl Citrate 0.9 Talc 3.3 Purified Water*41.0 Solid Content 20.6 Polymer Content 16.4

[0249] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0250] Disperse triethyl citrate (TEC) in the purified water.

[0251] Add the talc in the triethyl citrate dispersion.

[0252] Homogenize the dispersion using a homogenizer.

[0253] Add slowly the Eudragit® FS 30D dispersion to the talc/TECdispersion with stirring.

[0254] Continue to stir the coating dispersion until the coating processis complete.

[0255] Coating Conditions for the Application of Eudragit FS30D AqueousCoating Dispersion

[0256] The following coating parameters were used for coating with eachof the Eudragit® FS 30 D aqueous film coating. Coating Equipment STREA1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.2 mmMaterial Charge 300 gram Inlet Air Temperature 38° C. Outlet AirTemperature 22° C. Atomization Air Pressure 1.6 Bar Pump Rate 6 gram perminute

[0257] Coat pellets with Eudragit FS 30D coating dispersion dispersionsuch that you apply 30% coat weight gain to the pellets.

[0258] Clarithromycin Pellet Formulation and Preparation Procedure

[0259] Pellet Formulation

[0260] The composition of the clarithromycin pellets provided in Table16. TABLE 16 Composition of Clarithromycin Pellets Component Percentage(%) Clarithromycin 77.0 Lactose monohydrate, spray dried 11.0Croscarmellose sodium 5.0 Polyoxyl 35 Castor Oil* 5.0 Hydroxypropylmethylcellulose* 2.0 Purified water * Total 100

[0261] Preparation Procedure for Clarithromycin Pellets

[0262] Prepare the binder solution by adding the Polyoxyl to thepurified water while stirring. After that is mixed, slowly add thehydroxypropyl methylcellulose and continue to stir until a solution isachieved.

[0263] Blend clarithromycin, lactose monohydrate, and croscarmellosesodium using a Robot Coupe high shear granulator.

[0264] Add binder solution slowly into the powder blend under continuousmixing.

[0265] Granulate the powders in the high shear granulator with thebinder solution.

[0266] Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0267] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0268] Dry the spheronized pellets at 50° C. until the moisture level is>3%.

[0269] Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0270] Clarithromycin Enteric-Release Pellet Formulation and PreparationProcedure

[0271] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D AqueousCoating Dispersion Dispersion Formulation

[0272] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30Daqueous coating dispersion applied to the clarithromycin pellets isprovided below in Table 17. TABLE 17 Eudragit ® L 30 D-55/Eudragit NE30D Aqueous Coating Dispersion Component Percentage (%) Eudragit ® L30D-55 44.4 Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9Purified Water* 38.6 Solid Content 20.6 Polymer Content 16.4

[0273] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30DAqueous Dispersion

[0274] Heat purified water to 75-80° C. and then add triethyl citrate(TEC) and Imwitor 900. Homogenize dispersion until temperature is lessthan 55° C.

[0275] The TEC/Imwitor 900 dispersion is then stirred until thetemperature is less than 35° C.

[0276] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latexdispersion and stir for at least 30 minutes.

[0277] Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900dispersion and stir for at least 10 minutes.

[0278] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0279] Continue to stir the dispersion until the coating process iscomplete.

[0280] Coating Conditions for the Application of EudragitL30D-55/Eudragit NE 30DAqueous Coating Dispersion

[0281] The following coating parameters were used for coating of theEudragit® L 30 D-55/Eudragit NE30D film coating dispersion. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 45° C.Outlet Air Temperature 32 to 35° C. Atomization Air Pressure 1.6 BarPump Rate 3-4 gram per minute

[0282] Coat clarithromycin pellets with Eudragit L30 D-55/Eudragit NE30D film coating dispersion such that you apply 20% coat weight gain tothe pellets.

[0283] Clarithromycin Delayed Enteric-Release Pellets Formulation andPreparation Procedure

[0284] Preparation of an AQOAT AS-HF Aqueous Coating Dispersion

[0285] Dispersion Formulation

[0286] The composition of the aqueous AQOAT AS-HF aqueous coatingdispersion applied to the clarithromycin pellets is provided below inTable 18. TABLE 18 AQOAT AS-HF Aqueous Coating Dispersion ComponentPercentage (%) AQOAT AS-HF 7.0 Triethyl Citrate 2.0 Talc 2.1 Sodiumlauryl sulfate 0.2 Purified Water* 88.7 Solid Content 11.3 PolymerContent 7.0

[0287] Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion

[0288] Add triethyl citrate (TEC) to the purified water with stirring.

[0289] Add the sodium lauryl sulfate (SLS) to the TEC dispersion withstirring and completely until completely dissolved.

[0290] Add the AQOAT to the TEC/SLS dispersion and stir for at least 30minutes.

[0291] Add the talc to the AQOAT dispersion and until completely mixedand for at least 30 minutes.

[0292] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0293] Continue to stir the dispersion until the coating process iscomplete.

[0294] Coating Conditions for the Application of AQOAT AS-HF AqueousCoating Dispersion

[0295] The following coating parameters were used for coating of theAQOAT AS-HF film coating dispersion. Coating Equipment STREA 1 ™ TableTop Laboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm MaterialCharge 300 gram Inlet Air Temperature 48° C. Outlet Air Temperature 27°C. Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram per minute

[0296] Coat clarithromycin pellets with AQOAT AS-HF film coatingdispersion such that you apply 30-35% coat weight gain to the pellets.

[0297] Clarithromycin Colonic-Release Pellets Formulation andPreparation Procedure

[0298] Preparation of an Eudragit® FS30D Aqueous Coating DispersionDispersion Formulation

[0299] The composition of the aqueous Eudragit® FS 30D dispersionapplied to the clarithromycin pellets is provided below in Table 19.TABLE 19 Eudragit ® FS 30D Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® FS 30D 54.8 Triethyl Citrate 0.9 Talc 3.3Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4

[0300] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0301] Disperse triethyl citrate (TEC) in the purified water.

[0302] Add the talc in the triethyl citrate dispersion.

[0303] Homogenize the dispersion using a homogenizer.

[0304] Add slowly the Eudragit® FS 30D dispersion to the talc/TECdispersion with stirring.

[0305] Continue to stir the coating dispersion until the coating processis complete.

[0306] Coating Conditions for the Application of Eudragit FS30D AqueousCoating Dispersion

[0307] The following coating parameters were used for coating with eachof the Eudragit® FS 30 D aqueous film coating. Coating Equipment STREA1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.2 mmMaterial Charge 300 gram Inlet Air Temperature 38° C. Outlet AirTemperature 22° C. Atomization Air Pressure 1.6 Bar Pump Rate 6 gram perminute

[0308] Coat pellets with Eudragit FS 30D coating dispersion dispersionsuch that you apply 30% coat weight gain to the pellets.

[0309] Amoxicillin and Clarithromycin Tablets

[0310] Preparation of Amoxicillin and Clarithromycin Granulation forTableting TABLE 20 Composition of Amoxicillin and ClarithromycinGranulation (Immediate Release) Component Percentage (%) AmoxicillinTrihydrate powder 22.0 Clarithromycin 22.0 Lactose monohydrate, spraydried 45.0 Avicel PH 101 10.0 Hydroxypropyl methylcellulose, NF* 1.0Total 100

[0311] Blend Amoxicillin, Clarithromycin, lactose, and Avicel® PH 101using a high shear mixer.

[0312] Add the hydroxypropyl methylcellulose binder solution slowly intothe powder blend under continuous mixing.

[0313] Dry the granulation at 60° C. using a fluid bed dryer until theexhaust temperature reaches 40° C.

[0314] Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0315] Tableting of the Amoxicillin and Clarithromycin TABLE 21Composition of Amoxicillin and Clarithromycin Tablets ComponentPercentage (%) Amoxicillin/Clarithromycin granules 45.0 Avicel PH 2007.5 Eudragit L30D-55/NE 30D coated Amoxicillin Pellets 6.4 EudragitL30D-55/NE 30D coated Clarithromycin Pellets 7.6 AQOAT coatedAmoxicillin Pellets 7.2 AQOAT coated Clarithromycin Pellets 8.6 EudragitFS 30D coated Amoxicillin Pellets 6.9 Eudragit FS 30D coatedClarithromycin Pellets 8.3 Colloidal silicon dioxide 1.5 Magnesiumstearate 1.0 Total 100

[0316] Blend the Amoxicillin/Clarithromycin granules, Avicel PH-200,Amoxicillin coated pellets, Clarithromycin coated pellets and colloidalsilicon dioxide for 15 minutes in a tumble blender.

[0317] Add the magnesium stearate to the blender, and blend for 5minutes.

[0318] Compress the blend on a rotary tablet press.

[0319] The fill weight should be adjusted to achieve a 500 mg total dosetablet.

Example 47

[0320] Amoxicillin Pellet Formulation and Preparation Procedure

[0321] Pellet Formulations

[0322] The composition of the Amoxicillin trihydrate pellets provided inTable 22. TABLE 22 Composition of Amoxicillin Pellets ComponentPercentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 101 6.0Polyoxyl 35 Castor Oil* 1.0 Hydroxypropyl methylcellulose, NF* 1.0Purified Water ** Total 100

[0323] Preparation Procedure for Amoxicillin Pellets

[0324] Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

[0325] Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oilbinder solution slowly into the powder blend under continuous mixing.

[0326] Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator is 0.8 mm.

[0327] Spheronize the extrudate using a QJ-230 Spheronizer using a smallcross section plate.

[0328] Dry the spheronized pellets at 60° C. using a fluid bed dryeruntil the exhaust temperature reaches 40° C.

[0329] Pellets between 20 and 40 Mesh were collected for furtherprocessing.

[0330] Amoxicillin Delayed Enteric-Release Pellets Formulation andPreparation Procedure

[0331] Preparation of an AQOAT AS-HF Aqueous Coating Dispersion

[0332] Dispersion Formulation

[0333] The composition of the aqueous AQOAT AS-HF aqueous coatingdispersion applied to the amoxicillin pellets is provided below in Table23. TABLE 23 AQOAT AS-HF Aqueous Coating Dispersion Component Percentage(%) AQOAT AS-HF 7.0 Triethyl Citrate 2.0 Talc 2.1 Sodium lauryl sulfate0.2 Purified Water* 88.7 Solid Content 11.3 Polymer Content 7.0

[0334] Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion

[0335] Add triethyl citrate (TEC) to the purified water with stirring.

[0336] Add the sodium lauryl sulfate (SLS) to the TEC dispersion withstirring and completely until completely dissolved.

[0337] Add the AQOAT to the TEC/SLS dispersion and stir for at least 30minutes.

[0338] Add the talc to the AQOAT dispersion and until completely mixedand for at least 30 minutes.

[0339] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0340] Continue to stir the dispersion until the coating process iscomplete.

[0341] Coating Conditions for the Application of AQOAT AS-HF AqueousCoating Dispersion

[0342] The following coating parameters were used for coating of theAQOAT AS-HF film coating dispersion. Coating Equipment STREA 1 ™ TableTop Laboratory Fluid Bed Coater Spray nozzle diameter 1.0 mm MaterialCharge 300 gram Inlet Air Temperature 48° C. Outlet Air Temperature 27°C. Atomization Air Pressure 1.6 Bar Pump Rate 3-4 gram per minute

[0343] Coat amoxicillin pellets with AQOAT AS-HF film coating dispersionsuch that you apply 30-35% coat weight gain to the pellets.

[0344] Clarithromycin Pellet Formulation and Preparation Procedure

[0345] Pellet Formulation

[0346] The composition of the clarithromycin pellets provided in Table24. TABLE 24 Composition of Clarithromycin Pellets Component Percentage(%) Clarithromycin 77.0 Lactose monohydrate, spray dried 11.0Croscarmellose sodium 5.0 Polyoxyl 35 Castor Oil* 5.0 Hydroxypropylmethylcellulose* 2.0 Purified water * Total 100

[0347] Preparation Procedure for Clarithromycin Pellets

[0348] Prepare the binder solution by adding the Polyoxyl to thepurified water while stirring. After that is mixed, slowly add thehydroxypropyl methylcellulose and continue to stir until a solution isachieved.

[0349] Blend clarithromycin, lactose monohydrate, and croscarmellosesodium using a Robot Coupe high shear granulator.

[0350] Add binder solution slowly into the powder blend under continuousmixing.

[0351] Granulate the powders in the high shear granulator with thebinder solution.

[0352] Extrude the wet mass using an LCI Bench Top Granulator. Thediameter of the screen of the Bench Top Granulator was 1.0 mm.

[0353] Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

[0354] Dry the spheronized pellets at 50° C. until the moisture level is>3%.

[0355] Pellets between 16 and 30 Mesh were collected for furtherprocessing.

[0356] Clarithromycin Enteric-Release Pellet Formulation and PreparationProcedure

[0357] Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D AqueousCoating Dispersion

[0358] Dispersion Formulation

[0359] The composition of the aqueous Eudragit L30D-55/Eudragit NE 30Daqueous coating dispersion applied to the clarithromycin pellets isprovided below in Table 25. TABLE 25 Eudragit ® L 30 D-55/Eudragit NE30D Aqueous Coating Dispersion Component Percentage (%) Eudragit ® L30D-55 44.4 Eudragit NE 30D 14.8 Triethyl Citrate 1.3 Imwitor 900 0.9Purified Water* 38.6 Solid Content 20.6 Polymer Content 16.4

[0360] Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30DAqueous Dispersion

[0361] Heat purified water to 75-80° C. and then add triethyl citrate(TEC) and Imwitor 900. Homogenize dispersion until temperature is lessthan 55° C.

[0362] The TEC/Imwitor 900 dispersion is then stirred until thetemperature is less than 35° C.

[0363] Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latexdispersion and stir for at least 30 minutes.

[0364] Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900dispersion and stir for at least 10 minutes.

[0365] Screen the dispersion through a No. 60 mesh sieve prior tocoating.

[0366] Continue to stir the dispersion until the coating process iscomplete.

[0367] Coating Conditions for the Application of EudragitL30D-55/Eudragit NE 30DAqueous Coating Dispersion

[0368] The following coating parameters were used for coating of theEudragit® L 30 D-55/Eudragit NE30D film coating dispersion. CoatingEquipment STREA 1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzlediameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 45° C.Outlet Air Temperature 32 to 35° C. Atomization Air Pressure 1.6 BarPump Rate 3-4 gram per minute

[0369] Coat clarithromycin pellets with Eudragit L30 D-55/Eudragit NE30D film coating dispersion such that you apply 20% coat weight gain tothe pellets.

[0370] Clarithromycin Colonic-Release Pellets Formulation andPreparation Procedure

[0371] Preparation of an Eudragit® FS30D Aqueous Coating DispersionDispersion Formulation

[0372] The composition of the aqueous Eudragit® FS 30D dispersionapplied to the clarithromycin pellets is provided below in Table 26.TABLE 26 Eudragit ® FS 30D Aqueous Coating Dispersion ComponentPercentage (%) Eudragit ® FS 30D 54.8 Triethyl Citrate 0.9 Talc 3.3Purified Water* 41.0 Solid Content 20.6 Polymer Content 16.4

[0373] Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion

[0374] Disperse triethyl citrate (TEC) in the purified water.

[0375] Add the talc in the triethyl citrate dispersion.

[0376] Homogenize the dispersion using a homogenizer.

[0377] Add slowly the Eudragit® FS 30D dispersion to the talc/TECdispersion with stirring.

[0378] Continue to stir the coating dispersion until the coating processis complete.

[0379] Coating Conditions for the Application of Eudragit FS30D AqueousCoating Dispersion

[0380] The following coating parameters were used for coating with eachof the Eudragit® FS 30 D aqueous film coating. Coating Equipment STREA1 ™ Table Top Laboratory Fluid Bed Coater Spray nozzle diameter 1.2 mmMaterial Charge 300 gram Inlet Air Temperature 38° C. Outlet AirTemperature 22° C. Atomization Air Pressure 1.6 Bar Pump Rate 6 gram perminute

[0381] Coat pellets with Eudragit FS 30D coating dispersion dispersionsuch that you apply 30% coat weight gain to the pellets.

[0382] Amoxicillin and Clarithromycin Tablets

[0383] Preparation of Amoxicillin Granulation for Tableting TABLE 27Composition of Amoxicillin Granulation (Immediate Release) ComponentPercentage (%) Amoxicillin Trihydrate powder 22.0 Lactose monohydrate,spray dried 57.0 Avicel PH 101 20.0 Hydroxypropyl methylcellulose, NF*1.0 Total 100

[0384] Blend Amoxicillin, lactose, and Avicel® PH 101 using a high shearmixer.

[0385] Add the hydroxypropyl methylcellulose binder solution slowly intothe powder blend under continuous mixing.

[0386] Dry the granulation at 60° C. using a fluid bed dryer until theexhaust temperature reaches 40° C.

[0387] Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0388] Tableting of the Amoxicillin and Clarithromycin TABLE 28Composition of Amoxicillin and Clarithromycin Tablets ComponentPercentage (%) Amoxicillin granules 45.0 Avicel PH 200 7.5 EudragitL30D-55/NE 30D coated Clarithromycin Pellets 14.9 AQOAT coatedAmoxicillin Pellets 14.0 Eudragit FS 30D coated Clarithromycin Pellets16.1 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 100

[0389] Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin coatedpellets, Clarithromycin coated pellets and colloidal silicon dioxide for15 minutes in a tumble blender.

[0390] Add the magnesium stearate to the blender, and blend for 5minutes.

[0391] Compress the blend on a rotary tablet press.

[0392] The fill weight should be adjusted to achieve a 500 mg total dosetablet.

[0393] Clarithromycin and Amoxicillin Tablets

[0394] Preparation of Clarithromycin Granulation for Tableting TABLE 29Composition of Clarithromycin Granulation (Immediate Release) ComponentPercentage (%) Clarithromycin powder 22.0 Lactose monohydrate, spraydried 57.0 Avicel PH 101 20.0 Hydroxypropyl methylcellulose, NF* 1.0Total 100

[0395] Blend Clarithromycin, lactose, and Avicel® PH 101 using a highshear mixer.

[0396] Add the hydroxypropyl methylcellulose binder solution slowly intothe powder blend under continuous mixing.

[0397] Dry the granulation at 60° C. using a fluid bed dryer until theexhaust temperature reaches 40° C.

[0398] Granules between 20 and 40 Mesh are collected for furtherprocessing.

[0399] Tableting of the Amoxicillin and Clarithromycin TABLE 30Composition of Amoxicillin and Clarithromycin Tablets ComponentPercentage (%) Clarithromycin granules 45.0 Avicel PH 200 7.5 EudragitL30D-55/NE 30D coated Amoxicillin Pellets 14.9 AQOAT coatedClarithromycin Pellets 14.0 Eudragit ES 30D coated Amoxicillin Pellets16.1 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 100

[0400] Blend the Clarithromycin granules, Avicel PH-200, Amoxicillincoated pellets, Clarithromycin coated pellets and colloidal silicondioxide for 15 minutes in a tumble blender.

[0401] Add the magnesium stearate to the blender, and blend for 5minutes.

[0402] Compress the blend on a rotary tablet press.

[0403] The fill weight should be adjusted to achieve a 500 mg total dosetablet.

[0404] In one embodiment, Amoxicillin will be dosed in an alternatepulse to Clarithromycin. This will alternate the exposure to thebacteria in such a way as to make both antibiotics more effective thanif they were co-administered, and thereby competing with each other forsites on the bacterial cell wall receptors, or sites within thebacterial cells.

[0405] In addition, even when Amoxicillin and Clarithromycin are notdelivered in alternate pulses, the dosage forms as hereinabove describedprovide for improved treatment of infection.

[0406] Numerous modifications and variations of the present inventionare possible in light of the above teachings; therefore, within thescope of the appended claims, the invention may be practiced otherwisethan as particularly described.

We claim:
 1. A once-a-day antibiotic product comprising: first, second,and third dosage forms, wherein each of said dosage forms includes atleast one antibiotic and a pharmaceutically acceptable carrier; one ofsaid dosage forms includes at least a first antibiotic and another ofsaid dosage forms includes at least a second antibiotic that isdifferent from the first antibiotic; wherein said first and secondantibiotics are each selected from the group consisting of proteinsynthesis inhibiting antibiotics and non-protein synthesis inhibitingantibiotics; and wherein when said first antibiotic is a proteinsynthesis inhibiting antibiotic said second antibiotic is a non-proteinsynthesis inhibiting antibiotic; and wherein when said first antibioticis a non-protein synthesis inhibiting antibiotic said second antibioticis a protein synthesis inhibiting antibiotic; said first dosage form isselected from the group consisting of immediate release dosage forms anddelayed release dosage forms; said second and third dosage forms aredelayed release dosage forms; each of said first, second, and thirddosage forms initiates release of antibiotic at different times and Cmaxin serum of the total antibiotic released from said antibiotic productis achieved in less than about 12 hours from administration; and saidonce-a-day antibiotic product contains the total dosage of said firstand second antibiotics for a twenty-four hour period.
 2. The product ofclaim 1, wherein the first dosage form is an immediate release dosageform.
 3. The product of claim 2, wherein antibiotic released from thesecond dosage form reaches a Cmax in serum after antibiotic releasedfrom the first dosage reaches a Cmax in serum.
 4. The product of claim3, wherein antibiotic released form the third dosage form reaches a Cmaxin serum after antibiotic released from the second dosage form reachesCmax in serum.
 5. The product of claim 2, wherein the first dosage formincludes the first antibiotic, the second dosage form includes the firstand second antibiotics, and the third dosage form includes the secondantibiotic.
 6. The product of claim 2, wherein the immediate releasedosage form contains from 20% to 50% of the total dosage of antibiotic.7. The product of claim 2, wherein said second dosage form initiatesrelease of antibiotic before said third dosage form, wherein said seconddosage form provides from 30% to 60% by weight of the total antibioticreleased by said second and third dosage forms, and wherein said thirddosage form provides the remainder of the total antibiotic released bysaid second and third dosage forms.
 8. The product of claim 2, whereinantibiotic released from the second dosage form reaches a Cmax in serumin no more than about 4 hours after administration of the product. 9.The product of claim 2, wherein antibiotic released from the thirddosage form reaches a Cmax in serum within 8 hours after administrationof the product.
 10. The product of claim 2, wherein the product is anoral dosage form.
 11. The product of claim 2, further comprising afourth dosage form, said fourth dosage form comprising at least one ofsaid first and second antibiotics and a pharmaceutically acceptablecarrier.
 12. The product of claim 2, further comprising: a fourth dosageform, and wherein said first dosage form contains said first antibiotic;said second dosage form contains said first antibiotic; said thirddosage form contains said second antibiotic; said fourth dosage formincludes said second antibiotic and a pharmaceutically acceptablecarrier; and said second and third dosage forms have release profileswhereby C_(max) in serum for the first antibiotic and C_(max) in serumfor the second antibiotic released from the second and third dosageforms respectively are reached later in time than C_(max) in serum isreached for the first antibiotic released from the first dosage form,and whereby the C_(max) in serum for the second antibiotic released fromthe fourth dosage form is reached at a time after C_(max) in serum forantibiotic released from each of the first, second, and third dosageforms are reached.
 13. The product of claim 12, wherein the firstantibiotic released from the second dosage form, and the secondantibiotic released from the third dosage form reach a C_(max) in serumat about the same time.
 14. The product of claim 12, wherein said fourthdosage form is a sustained release dosage form.
 15. The product of claim12, wherein said fourth dosage form is a delayed release dosage form.16. The product of claim 15, wherein the immediate release dosage formcontains from 15% to 30% of the total dosage of antibiotic.
 17. Theproduct of claim 15, wherein said second dosage form initiates releaseof antibiotic before said third dosage form; wherein said third dosageform initiates release of antibiotic before said fourth dosage form;wherein said second dosage form provides 20% to 35% by weight of thetotal antibiotic released by said second, third, and fourth dosageforms; wherein said third dosage form provides from 20% to 40% by weightof the total antibiotic released by said second, third, and fourthdosage forms; and wherein said fourth dosage form provides the remainderof the total antibiotic released by said second, third, and fourthdosage forms.
 18. The product of claim 12, wherein antibiotic releasedfrom the second dosage form reaches a Cmax in serum in no more thanabout 4 hours after administration of the product.
 19. The product ofclaim 12, wherein antibiotic released from the third dosage form reachesa Cmax in serum within 8 hours after administration of the product. 20.The product of claim 12, wherein the product is an oral dosage form. 21.The antibiotic product of claim 2, wherein each of the first, second,and third dosage forms includes at least one of the first and secondantibiotics.
 22. The product of claim 21, wherein antibiotic releasedfrom the second dosage form reaches a Cmax in serum after antibioticreleased from the first dosage form reaches a Cmax in serum.
 23. Theproduct of claim 21, wherein antibiotic released from the third dosageform reaches a Cmax in serum after antibiotic released from the seconddosage form reaches a Cmax in serum.
 24. The product of claim 21,wherein the immediate release dosage form contains from 20% to 50% ofthe total dosage of antibiotic.
 25. The product of claim 21, whereinsaid second dosage form initiates release of antibiotic before saidthird dosage form, wherein said second dosage form provides from 30% to60% by weight of the total antibiotic released by said second and thirddosage forms, and wherein said third dosage form provides the remainderof the total antibiotic released by said second and third dosage forms.26. The product of claim 21, wherein antibiotic released from the seconddosage form reaches a Cmax in serum in no more than about 4 hours afteradministration of the product.
 27. The product of claim 21, whereinantibiotic released from the third dosage form reaches a Cmax in serumwithin 8 hours after administration of the product.
 28. The product ofclaim 21, wherein the product is an oral dosage form.
 29. The product ofclaim 2, wherein each of the first, second, and third dosage formscontains only one antibiotic.
 30. The product of claim 29, wherein thefirst dosage form contains clarithromycin, the second dosage formcontains amoxicillin, and the third dosage form contains clarithromycin.31. The product of claim 3, wherein antibiotic released from the thirddosage form reaches a Cmax in serum after antibiotic released from thesecond dosage form reaches a Cmax in serum.
 32. The product of claim 29,wherein antibiotic released from the third dosage form reaches a Cmax inserum after antibiotic released from the second dosage form reaches aCmax in serum, and wherein antibiotic released from the second dosageform reaches a Cmax in serum after antibiotic released from the firstdosage form reaches a Cmax in serum.
 33. The product of claim 29,wherein antibiotic released from the second dosage form reaches a Cmaxin serum after antibiotic released from the first dosage form reaches aCmax in serum.
 34. A once-a-day antibiotic product comprising: first,second, third, and fourth dosage forms, wherein each of said dosageforms includes one of a first antibiotic and a second antibiotic, and apharmaceutically acceptable carrier; wherein said first and secondantibiotics are each selected from the group consisting of proteinsynthesis inhibiting antibiotics and non-protein synthesis inhibitingantibiotics; and wherein when said first antibiotic is a proteinsynthesis inhibiting antibiotic said second antibiotic is a non-proteinsynthesis inhibiting antibiotic; and wherein when said first antibioticis a non-protein synthesis inhibiting antibiotic said second antibioticis a protein synthesis inhibiting antibiotic; wherein the first dosageform contains said first antibiotic and is free of said secondantibiotic; the second dosage form contains said second antibiotic andis free of said first antibiotic; the third dosage form contains saidfirst antibiotic and is free of said second antibiotic; and said fourthdosage form contains said second antibiotic and is free of said firstantibiotic; said first dosage form is selected from the group consistingof immediate release dosage forms and delayed release dosage forms; saidsecond, third, and fourth dosage forms are delayed release dosage forms;each of said first, second, third, and fourth dosage forms initiatesrelease of antibiotic at different times and Cmax in serum of the totalantibiotic released from said antibiotic product is achieved in lessthan about 12 hours from administration; and said once-a-day antibioticproduct contains the total dosage of said first and second antibioticsfor a twenty-four hour period.
 35. The product of claim 34, wherein thefirst dosage form is an immediate release dosage form.
 36. The productof claim 35, wherein each of the first, second, third, and fourth dosageforms contains only one antibiotic.
 37. The product of claim 36, whereinthe first dosage form contains clarithromycin, the second dosage formcontains amoxicillin, the third dosage form contains clarithromycin, andthe third dosage form contains amoxicillin.
 38. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 1 once-a-day.
 39. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 2 once-a-day.
 40. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 3 once-a-day.
 41. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 4 once-a-day.
 42. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 5 once-a-day.
 43. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 6 once-a-day.
 44. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 7 once-a-day.
 45. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 8 once-a-day.
 46. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 9 once-a-day.
 47. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 10 once-a-day.
 48. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 11 once-a-day.
 49. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 12 once-a-day.
 50. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 13 once-a-day.
 51. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 14 once-a-day.
 52. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 15 once-a-day.
 53. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 16 once-a-day.
 54. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 17 once-a-day.
 55. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 18 once-a-day.
 56. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 19 once-a-day.
 57. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 20 once-a-day.
 58. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 21 once-a-day.
 59. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 22 once-a-day.
 60. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 23 once-a-day.
 61. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 24 once-a-day.
 62. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 25 once-a-day.
 63. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 26 once-a-day.
 64. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 27 once-a-day.
 65. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 28 once-a-day.
 66. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 29 once-a-day.
 67. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 30 once-a-day.
 68. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 31 once-a-day.
 69. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 32 once-a-day.
 70. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 33 once-a-day.
 71. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 34 once-a-day.
 72. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 35 once-a-day.
 73. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 36 once-a-day.
 74. A process for treating abacterial infection in a host comprising: administering to the host theantibiotic product of claim 37 once-a-day.